Drug repurposing for cancer therapy

Abstract

Cancer, a complex and multifactorial disease, presents a significant challenge to global health. Despite significant advances in surgical, radiotherapeutic and immunological approaches, which have improved cancer treatment outcomes, drug therapy continues to serve as a key therapeutic strategy. However, the clinical efficacy of drug therapy is often constrained by drug resistance and severe toxic side effects, and thus there remains a critical need to develop novel cancer therapeutics. One promising strategy that has received widespread attention in recent years is drug repurposing: the identification of new applications for existing, clinically approved drugs. Drug repurposing possesses several inherent advantages in the context of cancer treatment since repurposed drugs are typically cost-effective, proven to be safe, and can significantly expedite the drug development process due to their already established safety profiles. In light of this, the present review offers a comprehensive overview of the various methods employed in drug repurposing, specifically focusing on the repurposing of drugs to treat cancer. We describe the antitumor properties of candidate drugs, and discuss in detail how they target both the hallmarks of cancer in tumor cells and the surrounding tumor microenvironment. In addition, we examine the innovative strategy of integrating drug repurposing with nanotechnology to enhance topical drug delivery. We also emphasize the critical role that repurposed drugs can play when used as part of a combination therapy regimen. To conclude, we outline the challenges associated with repurposing drugs and consider the future prospects of these repurposed drugs transitioning into clinical application.

Fig. 1

Tumoroids model in drug repurposing. a Schematic showing the generation of patient-derived organoids (PDOs) from a cancer biopsy: enzymatic digestion, embedding in extracellular matrix, addition of growth medium and cancer tumoroids enrichment by media compound withdrawal and/or addition of mutation related inhibitors. b, c The tumoroid model is used to screen drug repurposing candidates, resulting in the identification of drugs for preclinical and clinical testing. This figure was created with Biorender.com

Fig. 2

Diverse cancer hallmarks targeted by repurposed non-oncology drugs. Repurposed non-oncology candidates have shown great promise against cancer by targeting different hallmarks of cancer including sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, genome instability and mutation, tumor-promoting inflammation, reprogramming energy metabolism, evading immune destruction, unlocking phenotypic plasticity, non-mutational epigenetic regulation, polymorphic microbiomes, and senescent cells. This figure was created with Biorender.com

Fig. 3

Inducing cell death in cancers by repurposed non-oncology drugs. Regulated cell death (RCD) is a critical and active process that is controlled by specific signal transduction pathways and can be regulated by drug interventions. Repurposed non-oncology candidates can exert anticancer effects by inducing classical apoptosis and other RCD processes, such as ferroptosis, autophagy, necroptosis and pyroptosis. This figure was created with Biorender.com

Fig. 4

Classification of the tumor microenvironment. Underlying mechanisms of repurposed drugs targeting the specialized tumor microenvironments (TMEs). The TME can be divided into seven specialized microenvironments: hypoxic niche, immune microenvironment, metabolic microenvironment, acidic niche, innervated niche, mechanical microenvironment, and microbial microenvironment. Repurposed drugs with multi-targeted effects may reverse the effects of tumor-promoting microenvironments. TAM tumor-associated macrophage, CAF cancer-associated fibroblast, MDSC myeloid-derived suppressor cell, PNI perineural invasion, NK natural killer. This figure was created with Biorender.com

Fig. 5

Nanocarriers in repurposed drug delivery in cancer. Multiple nanocarriers including polymeric nanocarriers, mesoporous silica nanoparticles, polymeric micelles, liposomes, and metallic nanoparticles have shown promising effects in the delivery of repurposed therapeutics in cancer. Targeted cancer NP drug delivery systems: a Diversity of NPs in thedrug delivery platform. b Active-targeting ligand-decorated repurposed drug-loaded NPs for cancers. c Passive tumor targeting via the enhanced permeability and retention (EPR) effect. d Internalization of active-targeting NPs driven by receptor activation. This figure was created with Biorender.com